CN105017230A - Polysubstituted quinoline derivative and use thereof - Google Patents
Polysubstituted quinoline derivative and use thereof Download PDFInfo
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- CN105017230A CN105017230A CN201510362345.6A CN201510362345A CN105017230A CN 105017230 A CN105017230 A CN 105017230A CN 201510362345 A CN201510362345 A CN 201510362345A CN 105017230 A CN105017230 A CN 105017230A
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- IMRGIOWRTVOVPH-UHFFFAOYSA-N C1CCc2n[o]cc2CC1 Chemical compound C1CCc2n[o]cc2CC1 IMRGIOWRTVOVPH-UHFFFAOYSA-N 0.000 description 1
- KOAZFSFAZJBVEG-UHFFFAOYSA-N CS1C=C(CCCC2)C2=C1 Chemical compound CS1C=C(CCCC2)C2=C1 KOAZFSFAZJBVEG-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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Abstract
The invention belongs to the field of pharmaceutical chemistry, and provides a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor. The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor is a polysubstituted miazine statin fluorine-containing modifier of 1-fluoro-3-hydroxypentanoic acid and its salt or ester formed after ring opening of 3-fluoro-caprolactone fragment and its lactone. The structural formula of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor is shown in the specification. A result of test of like compounds shows that the compounds have an HMG-CoA reductase activity inhibition effect, and can be used as a new-generation latent HMG-CoA reductase inhibitor.
Description
Technical field
The invention belongs to medicinal chemistry art, particularly relate to a kind of statins, specifically fluorine-containing modifier of a kind of polysubstituted chinoline statin and uses thereof.
Background technology
Hyperlipidemia is the inducement of various cardiovascular and cerebrovascular diseases, population epidemiology investigation shows, for Chinese male crowd, low-density lipoprotein (in blood of human body lipid mostly and albumin bound form lipoprotein and exist) concentration often raises 1mmol/L that Incidence of CHD can be made to rise 36%, and ischemic cerebral apoplexy risk increases by 31%, in risk factors or its direct illness that the world today " three is high " (hyperlipidemia, hypertension, hyperglycemia) is various disease.Various medical science and biological metabolism research prove, 3-hydroxy-3-methyl penta 2 phthalein CoA-reductase (3-Hydroxy-3-methylglutaryl-CoA Reductase in blood of human body in the content of blood fat (lipoprotein) and liver, HMGR) activity has conclusive association: HMGR enzyme is with substrate 3-hydroxy-3-methyl penta 2 phthalein coenzyme A (3-Hydroxy-3-methylglutaryl-CoA, HMG-CoA) relate to the reduction reaction of four transfer transports for twice in conjunction with generation and generate critical materials 3, the 5-dihydroxy-acid of human body lipid synthesis.3-hydroxy-3-methyl penta 2 phthalein CoA-reductase inhibitors (namely commercially available statins) is the main flow blood lipid-lowering medicine that market is sold, be wherein 12,400,000,000 dollars by the atorvastatin calcium preparation of Pfizer Inc.'s development and sale by 2008 annual sales amounts, can be rated as " cookle " in medical history.The type medicine owing to can expose 3,5-identical dihydroxy-acid structures of same HMGR enzyme bound substrates HMG-CoA through metabolism in human body, and its binding ability with HMGR will be far longer than the normal substrate HMG-coA (K that HMG-CoA combines with HMGR simultaneously
mfor the umol/L order of magnitude, and the IC of statins
50at the nmol/L order of magnitude, namely such statins can fight for the active site of HMGR after entering human body, and then stops HMGR with the combination of HMG-coA, namely inhibits HMG-CoA to 3, the conversion of 5-dihydroxy-acid, and then the synthesis that finally inhibit people's body lipid.
Statins has been found to first-generation lovastatin since the U.S. develops list marketing by Merck & Co., Inc. from the fluvastatin of its proto-drug the most, and it experienced by natural fermented statin, synthetic statin, third generation superstatin three phases.Along with to the mechanism of action of statins and the research and development that deepens continuously of Computeraided drug design, recognize that introducing fluorine atom has effect in the suitable site of existing statins or its analogue to the HMGR enzyme inhibition activity improving drug molecule or the toxic side effect that reduces medicine.Foreign patent is as US Patent No. 5409820, US4965200, US5622985, US5691173, US20020183527, US4681893, US5354772, USRE37314, US685868, US6465447, US5753675, US5856336, US7022713, US5854259 and Canadian Patent CA1323836, the Chinese patent CN101580497A such as CA2072945, CN101230055A, CN1539417A and document (Science, 2001 (292): 1160-1164) 3S etc. has all directly or indirectly been asserted, 5R-3, 5-dihydroxy-acid structure is the activated necessary structure of this 3-hydroxy-3-methyl penta 2 phthalein CoA-reductase inhibitors (statins) tool, thus the Statins lipidemia medicine gone on the market on the market is all this class formation, existing patent also all remains this must structure
But statins also has untoward reaction, as: hepatopathy, carcinogenic toxicity, muscle side reaction, particularly rhabdomyolysis, just because of the toxic side effect that this is serious, make Cerivastatin (cerivastatin) remove city.
Summary of the invention
For above-mentioned technical problem of the prior art, the invention provides fluorine-containing modifier of a kind of polysubstituted chinoline statin and uses thereof, described fluorine-containing modifier of this polysubstituted chinoline statin and uses thereof will solve that statins of the prior art easily produces disease of the liver, carcinogenic toxicity, muscle side reaction, rhabdomyolysis technical problem.
The invention provides a kind of compound, its structural formula such as formula shown in I,
Wherein, R1, R2 is hydrogen, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group, R3, R4 is hydrogen, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group, R5, R6, R7, R8, R9, R10 is respectively hydrogen, hydroxyl, hydroxyl and carboxylate substituent groups formed by 1-3 carbon atom, the hydrocarbyl ether of 1-3 carbon atom, halogen, or the halohydrocarbon of 1-3 carbon atom, the hydrocarbyl group of 1-10 carbon atom of straight or branched, the naphthenic hydrocarbon of 3-7 carbon atom, substituted aroma ring, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group.
Further, in the hydrocarbyl group of 1-10 carbon atom of straight or branched, optionally replaced by one or more substituted radical, described substituting group is selected from: the simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched.
Further, in the naphthenic hydrocarbon of 3-7 carbon atom, optionally replaced by one or more substituted radical, described substituting group is selected from: the simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched.
Further, in substituted aroma ring, substituted radical comprises halogen, the alkyl of a 1-3 carbon atom or hydrocarbyl ether.
Further, described quinoline ring quilt
saturated, the unsaturated or fragrant rigid heterocyclic of five yuan or hexa-atomic substitutes.
Further, compound name of the present invention is called that its compound name is called (4S, 6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base) vinyl)-4-fluorine tetrahydrochysene-2H-pyran-2-one, its structural formula is as shown in 001
Further, compound name of the present invention is called (4S, 6R)-6-(2-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base) ethyl) the fluoro-tetrahydrochysene of-4--2H-pyran-2-one, its structural formula as shown in 002,
Present invention also offers a kind of pharmaceutical composition, the compound of above-mentioned (I) (001), (002) containing significant quantity or its salt or its ester, steric isomer or optically active isomer.
Present invention also offers the application of compound in the medicine for the preparation for the treatment of reduction blood lipid level of above-mentioned (I) (001), (002).
Present invention also offers the application of compound in the medicine for the preparation of the atherosclerosis for the treatment of coronary heart disease, hyperlipidemia initiation or the hyperlipidemia of diabetes initiation of above-mentioned (I) (001), (002).
Present invention also offers a kind of compound, its structural formula such as formula shown in I I,
Wherein, R1, R2 is hydrogen, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group, R3, R4 is hydrogen, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group, R5, R6, R7, R8, R9, R10 is respectively hydrogen, hydroxyl, hydroxyl and carboxylate substituent groups formed by 1-3 carbon atom, the hydrocarbyl ether of 1-3 carbon atom, halogen, or the halohydrocarbon of 1-3 carbon atom, the hydrocarbyl group of 1-10 carbon atom of straight or branched, the naphthenic hydrocarbon of 3-7 carbon atom, substituted aroma ring, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group, Z is hydrogen, the straight or branched alkyl of 1-10 carbon atom, the unitary of 1-20 carbon of straight or branched or polynary acyl group, the cyclic hydrocarbon radical of 3-7 carbon atom, substituting group aromaticacyl radical containing aromatic ring structure, or inorganic oxacid acyl group, M is sodium ion, potassium ion, ammonium ion, calcium ion, or magnesium ion.
Further, in the hydrocarbyl group of 1-10 carbon atom of straight or branched, optionally replaced by one or more substituted radical, described substituting group is selected from: the simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched.
Further, in the naphthenic hydrocarbon of 3-7 carbon atom, optionally replaced by one or more substituted radical, described substituting group is selected from: the simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched.
Further, in substituted aroma ring, substituted radical comprises halogen, the alkyl of a 1-3 carbon atom or hydrocarbyl ether.
Further, described quinoline ring quilt
saturated, the unsaturated or fragrant rigid heterocyclic of five yuan or hexa-atomic substitutes.
Further, compound name of the present invention is called (3S, 5S)-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base)-3-fluoro-5-hydroxyl-6-in heptan olefin(e) acid sodium salt, its structural formula as shown in 003,
Further, compound name of the present invention is called 3S, 5R)-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base)-3-fluoro-5-hydroxyheptanoic acid sodium salt, its structural formula as shown in 004,
Further, compound name of the present invention is called (3S, 5S, E)-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base) the fluoro-5-hydroxyl of-3--6-heptenoic acid half calcium salt, its structural formula as shown in 005,
Further, compound name of the present invention is called (3S, 5R)-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base)-3-fluoro-5-hydroxyheptanoic acid half calcium salt, its structural formula as shown in 006,
Present invention also offers a kind of pharmaceutical composition, the compound of above-mentioned (I I), (003) containing significant quantity, (004), (005), (006) or its salt or its ester, steric isomer or optically active isomer.
Present invention also offers the application of compound in the medicine for the preparation for the treatment of reduction blood lipid level of above-mentioned (I I), (003), (004), (005), (006).
Present invention also offers the application of compound in the medicine for the preparation of the atherosclerosis for the treatment of coronary heart disease, hyperlipidemia initiation or the hyperlipidemia of diabetes initiation of above-mentioned (I I), (003), (004), (005), (006).
Present invention also offers a kind of compound, its structural formula as shown in formula III,
Wherein, R1, R2 is hydrogen, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group, R3, R4 is hydrogen, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group, R5, R6, R7, R8, R9, R10, R11 is respectively hydrogen, hydroxyl, hydroxyl and carboxylate substituent groups formed by 1-3 carbon atom, the hydrocarbyl ether of 1-3 carbon atom, halogen, or the halohydrocarbon of 1-3 carbon atom, the hydrocarbyl group of 1-10 carbon atom of straight or branched, the naphthenic hydrocarbon of 3-7 carbon atom, substituted aroma ring, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group, X is hydrogen, the straight or branched alkyl of 1-10 carbon atom, the unitary of 1-20 carbon of straight or branched or polynary acyl group, the cyclic hydrocarbon radical of 3-7 carbon atom, substituting group aromaticacyl radical containing aromatic ring structure, or inorganic oxacid acyl group.
Further, in the hydrocarbyl group of 1-10 carbon atom of straight or branched, optionally replaced by one or more substituted radical, described substituting group is selected from: the simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched.
Further, in the naphthenic hydrocarbon of 3-7 carbon atom, optionally replaced by one or more substituted radical, described substituting group is selected from: the simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched.
Further, in substituted aroma ring, substituted radical comprises halogen, the alkyl of a 1-3 carbon atom or hydrocarbyl ether.
Further, described quinoline ring quilt
saturated, the unsaturated or fragrant rigid heterocyclic of five yuan or hexa-atomic substitutes.
Further, compound name of the present invention is called (3S, 5S, E)-methyl-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base) the fluoro-5-methyl of-3--6-hydroxyl heptenoic acid methyl esters, its structural formula as shown in 007,
Further, compound name of the present invention is called (3S, 5R)-methyl-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base)-3-fluoro-5-hydroxyheptanoic acid methyl esters, its structural formula as shown in 008,
Further, compound name of the present invention is called (3S, 5S, E)-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base) the fluoro-5-of-3-(methanoyl)-6-heptenoic acid, its structural formula as shown in 009,
Further, compound name of the present invention is called (3S, 5R)-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base) the fluoro-5-of-3-(methanoyl) enanthic acid, its structural formula as shown in 010,
Further, compound name of the present invention is called (3S, 5S, E)-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base) the fluoro-5-of-3-(nicotinylsalicylic oxygen)-6-heptenoic acid, its structural formula as shown in 011,
Further, compound name of the present invention is called (3S, 5R)-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base) the fluoro-5-of-3-(nicotinylsalicylic oxygen) enanthic acid, its structural formula as shown in 012,
Further, compound name of the present invention is called (3S, 5S, E)-(3S, 3AR, 6S, 6AS)-6-(nitre oxygen base) hexahydro furyl also [3,2b] furans-3-base-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base) the fluoro-5-methyl of-3--6-hydroxyl heptenoic acid esters, its structural formula is as shown in 013
Further, compound name of the present invention is called (3S, 5R)-(3S, 3AR, 6S, 6AS)-6-(nitre oxygen base) hexahydro furyl also [3,2b] furans-3-base 7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline pyridin-3-yl) the fluoro-5-hydroxyheptanoate of-3-, its structural formula is as shown in 014
Present invention also offers a kind of pharmaceutical composition, the compound of above-mentioned (III), (007) containing significant quantity, (008), (009), (010), (011), (012), (013), (014) or its salt or its ester, steric isomer or optically active isomer.
Present invention also offers the application of compound in the medicine for the preparation for the treatment of reduction blood lipid level of above-mentioned (III), (007), (008), (009), (010), (011), (012), (013), (014).
Present invention also offers the application of compound in the medicine for the preparation of the atherosclerosis for the treatment of coronary heart disease, hyperlipidemia initiation or the hyperlipidemia of diabetes initiation of above-mentioned (III), (007), (008), (009), (010), (011), (012), (013), (014).
The fluorine-containing modifier of polysubstituted chinoline statin of 1-fluoro-3-hydroxypentanoic acid containing being formed after 3-fluoro-caprolactone fragment and lactone open loop thereof of the present invention and salt or ester or its active metabolite, its structure is as shown in IV:
This compounds or its active metabolite are 3-hydroxy-3-methyl penta 2 phthalein CoA-reductase (3-Hydroxy-3-methylglutaryl-CoA Reductase, HMGR) the 3-hydroxyl of its six-membered cyclic lactone form of 3,5-dihydroxy-acids of inhibitor be replaced by fluorine atoms after derivative.Its structural formula such as formula I, wherein:
Part A is the fluoro-3-hydroxypentanoic acid of 1-and salt thereof or ester that are formed after 3-fluoro-caprolactone fragment or its lactone open loop;
Shown in I V, when its structure is the fluoro-caprolactone fragment of 3-, its substituent group R 1, R2 are the small volume substituted radicals such as the straight or branched alkyl of the straight chain of the 1-10 such as hydrogen, methyl, ethyl, propyl group, a vinyl carbon atom saturated or unsaturated alkyl or cyclopropyl, substituted-phenyl and the 1-10 such as methoxyl group, an oxyethyl group carbon atom, R1 and R2 is preferably hydrogen or methyl.
When its structure is the carboxylicesters of open loop form, its substituent group R 1, R2 are the saturated or unsaturated alkyl of the straight chains such as hydrogen, methyl, ethyl, propyl group, vinyl or cyclopropyl, substituted-phenyl and methoxyl group, oxyethyl group etc. small volume substituted radical, and R10 is preferably hydrogen.Become the R10 substituted radical of ester can be straight or branched alkyl or other organic acid acetic of 1-10 the carbon atoms such as methyl, ethyl, propyl group with carboxylic acid, be preferably methyl esters or ethyl ester.
Equally, hydroxy-acid group also can with basic metal or alkaline-earth metal M salify, and M metal-salt comprises the sodium salt of monovalence, sylvite or ammonium salt, the calcium salt of divalence, magnesium salts, particular certain cancers and calcium salt.
Can form organic or inorganic acid ester with radicals X addition for the alcoholic extract hydroxyl group exposed after lactone open loop, its implication is as follows:
A) organic acid acetic
The unitary of 1-20 carbon of-straight or branched or multi-carboxylate, a preferred 1-10 carbon, is optionally replaced by one or more substituted radical, and described substituting group is selected from: the simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched
Described substituting group also can be the cyclic hydrocarbon radical of 3-7 carbon atom, a preferred 3-5 carbon atom.
-substituting group aromatic carboxylic acid containing aromatic ring structure is as substituted aroma carboxylic acid:
Wherein n is the integer of 0-20, preferred 1-3;
X, Y represent substituting group, are selected from: the simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched
B) inorganic acid ester
Inorganic acid ester comprises various oxygen-containing inorganic acid ester, can be sulfuric acid, phosphoric acid, nitric acid, sulfurous acid, phosphorous acid, nitrous acid or pyrosulfuric acid, tetra-sodium etc., preferably sulfuric acid phosphoric acid and nitric acid.
C part is the rigid plane poly-substituted quinoline group of lipophilic, and structure is as shown in the formula showing.
In formula, specific definition is as follows:
A) female ring structure
-poly-substituted quinoline or other coplanar split heterocycles, be selected from quinoline, poly-substituted quinoline etc.
Saturated, the unsaturated or aromatic heterocycle of-following five yuan or hexa-atomic, comprise one or more heteroatoms being selected from nitrogen, oxygen, sulphur, such as, and poly-substituted quinoline part structure is with the ring structure of saturated, the unsaturated or aromatic heterocycle split of above-mentioned five yuan or hexa-atomic, is selected from:
Preferred following female ring structure:
B) substituting group in female ring structure
R5, R6, R7, R8, R9, R10 are defined as following substituted radical:
-unsubstituted, directly connects a hydrogen atom,
-hydroxyl, or hydroxyl and containing carboxylicesters formed by 1-3 carbon atom, preferably hydroxyl or hydroxy carboxylic acid ester, acetic ester,
The hydrocarbyl ether of-1-3 carbon atom, is preferably methoxyl group, the oxyethyl group of S steric configuration.
-halogen, or the halohydrocarbon of 1-3 carbon atom, be preferably fluorine or chlorine methyl.
The hydrocarbyl group of 1-10 carbon atom of-straight or branched, is optionally replaced by one or more substituted radical, and described substituting group is selected from: the simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched, is preferably sec.-propyl.
The naphthenic hydrocarbon of-3-7 carbon atom, optionally replaced by one or more substituted radical, described substituting group is selected from: the simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched, preferred cyclopropyl.
-substituted aroma ring, substituted radical comprises the alkyl of halogen, a 1-3 carbon atom.Be preferably fluorophenyl or the phenyl of para-orientation.
Part B is the syndeton of A and C part
-be the carbochain of two carbon atoms, can be vinyl or ethyl, be preferably ethyl.
The Drug combination of compound of the present invention and at least one Cardiovarscular, described medicine is selected from the medicines such as ACE inhibitor, Angiotensin Ⅱ receptor antagonist, beta adrenergic blocker, calcium ion channel blocker, antithrombotic agent.
The medicines such as suitable ACE inhibitor, Angiotensin Ⅱ receptor antagonist, beta adrenergic blocker, calcium ion channel blocker, antithrombotic agent can find it to describe in detail in such as clinical medicine handbook.
The preparation flow of compound of the present invention is as follows:
To include but not limited to that the carboxylic metallic salt (mainly calcium salt, sodium salt) of commercially available Statins bulk drug is for raw material, dissociates through certain density hcl acidifying, and obtain crude carboxylic acid through suitable organic solvent extraction final vacuum is concentrated.This crude product, without refining, namely carries out lactonizing of next step.
The DMAP of above-mentioned crude carboxylic acid and catalytic amount, the magnetic stir bar of suitable size joins in suitable reaction vessel, after organic solvent dissolution in the lump.Drip a certain amount of dicyclohexylcarbodiimide solution, stirred at ambient temperature reaction is spent the night.After thin-layer chromatography monitoring reacts completely, suction filtration, filtrate anhydrous sodium sulfate drying, concentrated, column chromatography for separation (PE/EA gradient elution) obtains lactone.
A certain amount of organic solvent and diethylin sulfur trifluoride join in reaction vessel, and a certain amount of lactone solution adds after stirring certain hour by low temperature.After for some time, natural temperature reaction is spent the night.After thin-layer chromatography monitoring reacts completely, add water cancellation, and separatory extracts, anhydrous sodium sulfate drying, concentrated, and column chromatography for separation (PE/EA gradient elution) obtains fluorine-containing derivant of the present invention.
By the lactone form of above-mentioned fluorine-containing derivant, open loop can obtain 1-fluoro-3-hydroxypentanoic acid form under suitable alkaline solution and organic solvent, thus expose Carboxylic acid and alcohol oh group, further with the affixture such as acid, alkali addition salify, ester, acid amides.
This kind of compou nd synthesis method of the present invention is simple, existing procucts bulk drug particularly can be utilized for raw material, simply react can obtain through a few step.Relative to the statin analogue (referring to HMGR enzyme inhibitors) of business development, its inhibitory enzyme activity IC
50value is compared or the same order of magnitude or have the lower order of magnitude, and which show this compounds of the present invention can as the medicinal application reducing blood fat.Particularly under all statins is external large-scale pharmacy giant patent monoply situation on the market, exploitation has the fluorine-containing statins antilipemic medicine of independent intellectual property right, has certain meaning.
Compound of the present invention is 3-hydroxy-3-methyl penta 2 phthalein CoA-reductase (3-Hydroxy-3-methylglutaryl-CoA Reductase, HMGR) inhibitor.
The present invention includes steric isomer and optically active isomer, such as corresponding isomer or diastereomer, its Producing reason is the asymmetry possessed in structure in this compounds selected.The same with most drug, it also can have crystal formation, and the different crystal forms that in this compounds, each single chemical substance has also all is included in class of the present invention.
This compounds of the present invention also can be the form of solvation, especially methyl alcohol, ethanol, the small molecule solvent of the larger polarity such as water.Its solvation can occur in the production process of the composition of this compound or inclusion compound, or the water absorbability had due to compound, solvation can occur through certain hour.
Compound of the present invention and active metabolite thereof are the derivatives being called as prodrug or metabolic activity thing.
The fluoro-3-hydroxypentanoic acid of the 1-formed after compound lactone open loop of the present invention has hydroxyl and hydroxy-acid group, can react change into corresponding salt with corresponding organic bases and mineral alkali in organic solvent (ethanol, acetone, methylene dichloride, tetrahydrofuran (THF) etc.).
The salt that mineral alkali becomes comprises sodium salt, calcium salt, sylvite, ammonium salt etc.Particular certain cancers and calcium salt.
There is after the open loop of the compounds of this invention lactone the fluoro-3-hydroxypentanoic acid of 1-, containing hydroxy-acid group and alcoholic OH groups, can add with suitable oxygen acid and alcohol compound and be shaped as ester.
After the open loop of the compounds of this invention lactone, hydroxyl can obtain carboxylicesters with oxygen acid addition, and these esters comprise the ester (these acid are reacted into ester with the alcoholic extract hydroxyl group exposed after lactone hydrolysis) obtained with organic or inorganic oxygen acid institute addition.These oxygen-containing inorganic acids include but not limited to (Asia) sulfuric acid, (Asia) phosphoric acid, nitric acid, carbonic acid, (former) silicic acid, and corresponding (Asia) hydrogen sulfuric acid ester, (Asia) hydrogen phosphate etc.Organic acid comprises simple alkyl acid as formic acid, acetic acid, propionic acid, hexanodioic acid, alginic acid, the amino acid such as aspartic acid, phenylformic acid, Phenylsulfonic acid, butyric acid, citric acid, dextrocamphoric acid, camphorsulfonic acid, cyclopentyl propionic acid, glucosulfone acid, dodecyl sulphate, ethyl sulfonic acid, fumaric acid, glucoheptonic acid, Phosphoric acid glycerol esters, enanthic acid, caproic acid, 2-ethylenehydrinsulfonic acid, lactic acid, toxilic acid, methylsulfonic acid, 2-naphthene sulfonic acid, oxalate, flutter acid, pectinic acid, 3-phenylpropionic acid, picric acid, PIVALIC ACID CRUDE (25), succsinic acid, tartrate, toluenesulphonic acids, palmitinic acid can be used for the parmacodynamics-less activities such as undeeanoic acid the organic carboxyl acid that same hydroxyl becomes ester.
After the open loop of the compounds of this invention lactone, carboxylic acid can add with suitable alcohol and is shaped as carboxylicesters.Organic Alcohol comprises simple alkyl alcohol as methyl alcohol, ethanol, propyl alcohol, hexylene glycol, the parmacodynamics-less activities such as glycerol can be used for the alcohols that same carboxylic acid becomes ester.
By the lactone form of above-mentioned fluorine-containing derivant, open loop can obtain 1-fluoro-3-hydroxypentanoic acid form, thus expose Carboxylic acid and alcohol oh group under suitable alkaline solution and organic solvent, hydroxyl wherein can same chlorsulfonic acid/pyridine, POCl
3/ N (Et)
3, wait reaction to generate inorganic sulfuric ester, phosphoric acid ester, nitric ether.
Indication of the present invention is that compound and active metabolite thereof include but not limited to the compound in claims to carry out split with existing known related drugs, these splits comprise and covalently boundly include but not limited to into ester, become acid amides to become complicated salt or the part A in formula I are carried out the splicing of fragment with other related drugs.All part A in structural formula carried out split with other medicine and has and suppress the compound of HMGR enzymic activity to be all analogue and the active metabolite thereof of indication in patent claims of the present invention 1.
Related drugs in above-mentioned includes but not limited to the various kinds of drug for preventing and treating three height (hyperlipidemia, hypertension, hyperglycemia).For patient clinically, one of three senior middle schools is not go out item separately, be usually that two or three appear at the different steps of patient disease simultaneously, thus drug combination is necessary, and this contributes to the toxic side effect reducing dose and alleviate medication treatment.
Above-mentioned middle related drugs includes but not limited to phenoxy acetic acid class, the nicotinic acid class for the treatment of hyperlipidemia.
Above-mentioned middle related drugs includes but not limited to treat hypertensive Mg-ATP enzyme inhibitors class (as serpentine), α
2receptor stimulant (as clonidine, methyldopa), beta-blockers (atenolol USP 23 as in Luo Er class), angiotensin-convertion enzyme inhibitor (benazepril as in pril), angiotensinⅡantagonist (telmisartan of class as smooth in sand), nitric oxide donors medicine (isosorbide mononitrate as nitrate esters) etc., these medicines all contain amido or alcoholic extract hydroxyl group, hydroxy-acid group, can become acid amides with compound of the present invention by being dehydrated into ester, soda acid salify obtains the medicine splicing object of being correlated with.
The present invention utilizes model prediction result in Computer-Aided Drug Design, the a series of statins fluorine-containing derivant containing 3S-fluoro-caprolactone fragment structure of design and synthesis, obviously this compounds can expose 3S after hydrolysis, 5R-3,5-dihydroxy-acid structure, through HMGR enzyme inhibition activity experiment test, find that this series compound has the statins same order of same commercial type or the IC of lower quantity
50test value, can be used as lipidemia medicine and uses.
HMGR inhibitor of the present invention (statins be namely commonly called as) be not only the toxic side effects will eliminated or at least weaken this kind of medicine and bring, and pharmacologically active value is improved.Pharmacology test result shows, in claim Compound Phase for not derivative statin on the whole to HMGR enzyme inhibition activity IC
50test value tool is significantly improved.
Embodiment:
The following example illustrates and unrestricted method and composition of the present invention.Other suitable amendments of different condition and product and adjustment are normal and approved.To those skilled in the art, obviously also within the scope of the invention.
Compound of the present invention can use suitable material to prepare as raw material according to the general approach of the following stated, and carrys out concrete example explanation by embodiment below.Certainly, the condition of the citing compound producing step in embodiment and the various known rational change of method also can for the preparation of these compounds.Except as otherwise noted, organic solvent used in embodiment and reagent (methylene dichloride, ethyl acetate, sherwood oil and triethylamine etc.) be commercial reagent and do except water treatment or the molecular sieve after using activation do Non-aqueous processing in a small amount through the ordinary method that this area is approved.Described analytical and testing instrument and condition unless otherwise stated: HRMS high resolution mass spectrum is Brooker,Switzerland company solanX-70 FT-MS, and H-NMR nucleus magnetic hydrogen spectrum volance III 500M, test solvent is CDCl
3.Spectral data is attached.
The generalized flowsheet of this compounds of preparation is described below:
To include but not limited to that the carboxylic metallic salt (mainly calcium salt, sodium salt) of commercially available Statins bulk drug is for raw material, dissociates through certain density hcl acidifying, and obtain crude carboxylic acid through suitable organic solvent extraction final vacuum is concentrated.This crude product, without refining, namely carries out lactonizing of next step.
The DMAP of above-mentioned crude carboxylic acid and catalytic amount, the magnetic stir bar of suitable size joins in suitable reaction vessel, after organic solvent dissolution in the lump.Drip a certain amount of dicyclohexylcarbodiimide solution, stirred at ambient temperature reaction is spent the night.After thin-layer chromatography monitoring reacts completely, suction filtration, filtrate anhydrous sodium sulfate drying, concentrated, column chromatography for separation (PE/EA gradient elution) obtains lactone.
A certain amount of organic solvent and diethylin sulfur trifluoride join in reaction vessel, and a certain amount of lactone solution solution adds after stirring certain hour by low temperature.After for some time, natural temperature reaction is spent the night.After thin-layer chromatography monitoring reacts completely, add water cancellation, and separatory extracts, anhydrous sodium sulfate drying, concentrated, and Silver Nitrate complexing silica gel column chromatography is separated (Virahol/sherwood oil gradient elution) and obtains fluorine-containing derivant of the present invention.
By the lactone form of above-mentioned fluorine-containing derivant, open loop can obtain 1-fluoro-3-hydroxypentanoic acid form under suitable alkaline solution and organic solvent, thus expose Carboxylic acid and alcohol oh group, further with the affixture such as acid, alkali addition salify, ester, acid amides.
Embodiment:
The preparation of embodiment 1 pitavastatin lactone
Take the pitavastatin calcium salt of 5.00g, join in the eggplant-shape bottle of 250ml, add the dilute hydrochloric acid of 20 times of dilutions of the methylene dichloride of 100ml and about 10ml, acidifying, separatory, 100ml methylene dichloride equivalent extracts three times, merge lower floor's organic phase, anhydrous sodium sulfate drying.Concentrated, oil pump vacuumizes, and obtains white powder 2.87g, i.e. pitavastatin crude carboxylic acid
Take the above-mentioned pitavastatin crude carboxylic acid of 2.50, join in there-necked flask, add the p dimethylamino pyridine of 0.05g, 50ml methylene dichloride and stirrer.The dicyclohexylcarbodiimide slowly injecting 3.0g under ice bath is dissolved in 20ml methylene dichloride gained solution.After dropwising, remove ice bath and react under room temperature and spend the night.After thin-layer chromatography monitoring reacts completely, suction filtration, filtrate anhydrous sodium sulfate drying, vacuum is spin-dried for, and rapid column chromatography is separated (PE/EA gradient elution) and obtains pitavastatin lactone 1.05g.MP:65.2-67.3 DEG C, HRMS (ESI): C
25h
22fNO
3, 404.13067 (M+H)
+, theoretical value is 404.13320, H-NMR:7.96 (d, 1H, J=8.4Hz), 7.61 (td, 1H, J=8.3,6.3,1.8Hz), 7.38-7.29 (m, 2H), 7.23-7.16 (m, 4H),
6.72(d,1H,J＝16.2Hz),5.61(dd,1H,J＝16.2,6.3Hz),5.19(t,1H,J＝6.4Hz),4.28-4.23(m,1H),2.71(dd,1H,J＝17.8,4.9Hz),2.61(dd,1H,J＝17.8,2.5Hz),2.42-2.35(m,1H),2.01(d,1H,J＝4.4Hz),1.93(dd,1H,J＝12.6,2.9Hz),1.19-1.11(m,2H),1.09-1.04(m,2H)。
The preparation of embodiment 2 compound 001,002
The magnetic stir bar of suitable size joins in the reaction tubes of 50ml; displaced air also uses nitrogen protection; reaction vessel is inserted low temperature stirring reaction bath (less than-65 DEG C) after injecting the methylene dichloride of 30ml; low temperature hemostasis adds the diethylin sulfur trifluoride of 0.75ml; the pitavastatin of 1.50g, after 15 minutes, is dissolved in 5ml dichloromethane solution and slowly adds by stir about.Stirring reaction is after about 30 minutes, and injection adds the triethylamine of about 0.3ml, and after 2 hours, natural temperature reaction is spent the night.After thin-layer chromatography monitoring reacts completely, suction filtration, filtrate anhydrous sodium sulfate drying, is spin-dried for, and Silver Nitrate complexing silica gel column chromatography is separated (Virahol/sherwood oil gradient elution) and obtains pitavastatin fluoro product (001) 0.76g.
The pitavastatin of 0.58g is dissolved in the methyl alcohol of 15ml, adds the 10%Pt/C hydrogenation catalyst of 50mg, and pressurization 1.5MPa, room temperature reaction spends the night.React completely, filtration catalizer, concentrates and is spin-dried for and obtains hydrogenation pitavastatin crude product 0.52g.Its HRMS (ESI) after purifying:: C
25h
24fNO
3, 406.18230 (M+H)
+, theoretical value is 406.18185; H-NMR (CDCl
3solvent, 500MHz): 8.02 – 7.88 (m, 1H), 7.57 (ddd, J=15.5,8.6,5.4Hz, 1H), 7.36 – 7.26 (m, 2H), 7.24 – 7.11 (m, 4H), 6.38 (d, J=16.1Hz, 1H), 5.59 (dt, J=14.2,7.0Hz, 1H), 3.81 (br s, OH), 2.58 – 2.35 (m, 3H), 2.22 (dd, J=19.2,6.6Hz, 1H), 1.69 – 1.44 (m, 2H), 1.38 – 1.20 (m, 4H), 1.03 (tt, J=11.6,3.0Hz, 2H; Crude product, according to embodiment 2, drops into hydrogenation pitavastatin crude product 0.50g, diethylin sulfur trifluoride 0.40ml, 0.2ml triethylamine.Last column chromatography obtains hydrogenation pitavastatin fluoro product (002) 0.36g
Embodiment 3 compound 003,004, the preparation of 005,006
Get pitavastatin fluoro thing (001) 1.00g, ice bath after dissolving with tetrahydrofuran (THF) 6ml, after the LiOH solution 1.5ml adding 1mol/L stirs 2 hours, when hcl acidifying with 10% is 2-3 to pH, 45 DEG C of steamings of reducing pressure desolventize, add acetone be about 10ml dissolve after, slowly while stirring drip 10% Na
2cO
3the aqueous solution, has floss and muddy appearance as seen, drops to till no longer there is floss.Be heated to muddy thing dissolve, leave standstill, slow cooling spends the night.Next day obtains needle crystal 0.68g, i.e. pitavastatin fluoro sodium salt (003).Same with the target compound 002 in embodiment 3 for substrate can obtain compound 004.
Get pitavastatin fluoro thing (001) 1.00g, ice bath after dissolving with tetrahydrofuran (THF) 6ml, after the LiOH solution 1.5ml adding 1mol/L stirs 2 hours, when hcl acidifying with 10% is 7-8 to pH, 45 DEG C of steamings of reducing pressure desolventize, add ethanol be about 10ml dissolve after, slowly while stirring drip 10% CaCl
2the aqueous solution, stirring is spent the night, and separate out solid, suction filtration, obtains half calcium salt crude product.With the methanol/water mixing solutions of 50% volume ratio, refined pitavastatin fluoro half calcium salt (005) 0.75g of recrystallization.In like manner can obtain compound 006.
The preparation of embodiment 4 compound 007,008
Get pitavastatin fluoro thing (001) 1.00g, ice bath after dissolving with tetrahydrofuran (THF) 6ml, after the LiOH solution 2.5ml adding 1mol/L stirs 2 hours, by this water oil mixt washed with diethylether three times (5 × 3), after washing, discard upper organic phase at every turn.Aqueous phase with 10% hcl acidifying be 2-3 to pH time, add water and ethyl acetate separatory extracts three times (6 × 3), organic phase anhydrous sodium sulfate drying, 45 DEG C of steamings of reducing pressure desolventize and obtain pitavastatin fluoro lactone open loop crude carboxylic acid 0.89g.
Above-mentioned crude carboxylic acid is dissolved in the anhydrous methanol of 25ml, after adding the p dimethylamino pyridine of catalytic amount, adds 1.2gDCC (dicyclohexylcarbodiimide) and be dissolved in 5ml methyl alcohol gained solution under ice bath.Remove ice bath, stirring reaction spends the night, and after thin-layer chromatography monitoring reacts completely, suction filtration, concentrating under reduced pressure, silica gel column chromatography separating purification obtains pitavastatin fluorocarboxylic acid methyl esters (007) 0.75g.Same method can obtain compound 008.
The preparation of embodiment 5 compound 009,0100
The lactone of pitavastatin fluoro described in Example 4 open loop crude carboxylic acid 0.65g is dissolved in the mixed solvent of the 1:1 of formic acid and methylene dichloride, after adding the p dimethylamino pyridine of catalytic amount, under ice bath, add the mixed solvent gained solution that 1.2gDCC (dicyclohexylcarbodiimide) is dissolved in the 1:1 of 5ml formic acid and methylene dichloride.Remove ice bath, stirring reaction spends the night, and after thin-layer chromatography monitoring reacts completely, suction filtration, concentrating under reduced pressure, silica gel column chromatography separating purification obtains pitavastatin fluorocarboxylic acid manthanoate (009) 0.57g.Same method can obtain compound 010.
The preparation of embodiment 6 compound 011,012
The lactone open loop crude carboxylic acid 0.65g of pitavastatin fluoro described in Example 4 and 2g nicotinic acid are dissolved in the methylene dichloride of 15ml, after adding the p dimethylamino pyridine of catalytic amount, add 1.2gDCC (dicyclohexylcarbodiimide) under ice bath and be dissolved in 5ml methylene dichloride gained solution.Remove ice bath, stirring reaction spends the night, and back flow reaction is after about 1 hour, and react completely through thin-layer chromatography monitoring, suction filtration, filtrate reduced in volume, silica gel column chromatography separating purification obtains pitavastatin fluoro nicotinate (011) 0.57g.
Same method can obtain compound 012.
The preparation of embodiment 7 compound 013,014
The lactone open loop crude carboxylic acid 0.65g of pitavastatin fluoro described in Example 4 and 2.5g isosorbide mononitrate are dissolved in the acetonitrile of 50ml, after adding the p dimethylamino pyridine of catalytic amount, add 1.2gDCC (dicyclohexylcarbodiimide) under ice bath and be dissolved in 5ml acetonitrile gained solution.Dropwise recession except ice bath, heating in water bath back flow reaction is spent the night, and react completely through thin-layer chromatography monitoring, suction filtration, filtrate reduced in volume, silica gel column chromatography separating purification obtains pitavastatin fluoro isosorbide mononitrate (013) 0.26g.Same method can obtain compound 014.
Compound activity is tested
Following description of test the compounds of this invention is to the restraining effect of the enzymic activity of HMG-CoA reductase (HMGR)
Experimental principle
3-hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductase enzyme is the key enzyme of this pathways metabolism of catalysis acetyl-CoA synthesis mevalonic acid in body, and it reacts below catalysis under physiological environment:
HMG-CoA+NADPH+2H
+→mevalonic acid+2NADP
++CoASH
Because NADPH has absorption peak at 340nm place, therefore the activity of HMG-CoA reductase can have been come by the reduction yield of division of labor photometry 340nm place's photoabsorption.
Material and instrument: (this test kit comprises HMG-CoA Reductase Assay Kit: HMGR, HMG-CoA, NADP-H, damping fluid, pitavastatin solution), other subsidiary material are 96 orifice plates, ultrapure water, accurate pipettor (each one of 2-20ul and 0.5-2ul) and supporting disposable rifle head, spectrophotometer or microplate reader
Medicament preparation and preparation
5 of 10ml times of concentration buffer liquid are diluted to 1 times of damping fluid (namely 5 times of liquid of 10ml add the ultrapure water of 40ml), when with 96 orifice plate, 1 times of liquid of 1ml can carry out the test of 5 samples, is stored in ice stand-by, and remaining 5 times of damping fluids are in-20 DEG C of preservations.The NADPH of 25mg needs 1 times of damping fluid of supplementary 1.5ml, mixes-20 DEG C of preservations.
Method and flow process
Thaw: thaw enzyme require more on ice or keep surrounding environment cooling, try not enzyme to be placed on ice more than 60 minutes, because long meeting storage period causes the activity of enzyme to reduce.Other thaw and can at room temperature carry out, and should be kept on ice once thaw.
Instrument adjustment: before experiment starts, temperature is adjusted to 37 DEG C, absorbing wavelength is 340nm, gets out dynamic routine.96 orifice plate samples read a number in every 20 seconds, amount to 10 minutes.
The form provided according to kit and flow process add the reaction solution of suitable volumes
Form
Reagent Standard entertion mode
Flow process: a, adds 1 times of quantitative damping fluid in each hole;
B, add testing sample in the hole except blank and positive control
C, add supplemented damping fluid NADPH in each hole
D, adds substrate HMG-CoA in each hole
E, enzyme-added HMGR is in the hole except blank
F, mixes reaction solution, especially with during 96 orifice plate test sample at least will before survey first time extinction ground strong stirring 10 seconds
G, opens dynamic routine, observes the change of absorbancy
Active testing is carried out according to the method that kit introduces, obtain absorbancy downcurve, the slope of decline indicates the inhibition of different sample to HMGR enzyme, carries out mathematics manipulation and matching to the slope curve of gained, according to the technical support of kit, by following formulae discovery activity data
Wherein: parameter 12.44 represents 12.44mM/cm, due to the rejection ratio of NADPH under 340nm, I is 6.22mM/cm, the NADPH of non-twice in reaction mechanism, therefore is 12.44
TV is the cumulative volume of reaction solution, and 96 orifice plates are 0.2ml
V represents the volume of reductase enzyme, enzyme enzyme milli-. the concentration in gram albumen, 0.55-0.65mg/ml
LP represents optical path width, and 96 orifice plates are 0.55cm
The NADPH that Unit is defined as per minute 1umol at 37 DEG C is converted into NADP
+, concrete unit is umol/min/mg protein
A340 represents the absorbancy of sample at 340 nano wave lengths, and Δ A340 represents corresponding absorbancy changing value
Mins
samplerepresent sample test time used, unit be minute, the Mins of correspondence
blankrepresent that blank sample tests the time used, the same Mins of its numerical value
sampleequal.
overall expression experienced by Mins
samplethe velocity of variation of sample absorbancy under wavelength 340 nanometer in time, unit is min
-1, same
represent the velocity of variation of blank sample.
Test result
Definition inhibiting rate is
Wherein activity data
activityrepresent the Activity activity value tested and calculated according to formula correspondence, activity data
samplerepresent the activity value after adding inhibitor sample.
Claims (38)
1. a compound, its structural formula is such as formula shown in I:
Wherein, substituent group R 1, R2 is hydrogen, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group, R3, R4 is hydrogen, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group, R5, R6, R7, R8, R9, R10 is respectively hydrogen, hydroxyl, containing 1-3 carbon atom carboxylic acid's ester substituted radical, the hydrocarbyl ether of 1-3 carbon atom, halogen, or the halohydrocarbon of 1-3 carbon atom, the hydrocarbyl group of 1-10 carbon atom of straight or branched, the naphthenic hydrocarbon of 3-7 carbon atom, substituted aroma ring, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group.
2. a kind of compound as claimed in claim 1, it is characterized in that: in the hydrocarbyl group of 1-10 carbon atom of straight or branched, optionally replaced by one or more substituted radical, described substituting group is selected from the simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched.
3. a kind of compound as claimed in claim 1, it is characterized in that: in the naphthenic hydrocarbon of 3-7 carbon atom, optionally replaced by one or more substituted radical, described substituting group is selected from: the simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched.
4. a kind of compound as claimed in claim 1, is characterized in that: in substituted aroma ring, and substituted radical comprises halogen, the alkyl of a 1-3 carbon atom or hydrocarbyl ether.
5. a kind of compound as claimed in claim 1, is characterized in that: described quinoline ring quilt
saturated, the unsaturated or fragrant rigid heterocyclic of five yuan or hexa-atomic substitutes.
6. a kind of compound as claimed in claim 1, it is characterized in that: its compound name is called (4S, 6S)-6-((E)-2-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base) vinyl)-4-fluorine tetrahydrochysene-2H-pyran-2-one, its structural formula is as shown in 001
7. a kind of compound as claimed in claim 1, it is characterized in that: its compound name is called (4S, 6R)-6-(2-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base) ethyl) the fluoro-tetrahydrochysene of-4--2H-pyran-2-one, its structural formula is as shown in 002
8. a pharmaceutical composition, arbitrary described compound or its salt or its ester, steric isomer or optically active isomer in the claim 1,6 or 7 containing significant quantity.
9. in claim 1,6 or 7, arbitrary described compound is reducing the application in the medicine of blood lipid level for the preparation for the treatment of.
10. the application of arbitrary described compound in the medicine for the preparation of the atherosclerosis for the treatment of coronary heart disease, hyperlipidemia initiation or the hyperlipidemia of diabetes initiation in claim 1,6 or 7.
11. 1 kinds of compounds, its structural formula such as formula shown in I I,
Wherein, R1, R2 is hydrogen, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group, R3, R4 is hydrogen, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group, R5, R6, R7, R8, R9, R10 is respectively hydrogen, hydroxyl, hydroxyl and carboxylate substituent groups formed by 1-3 carbon atom, the hydrocarbyl ether of 1-3 carbon atom, halogen, or the halohydrocarbon of 1-3 carbon atom, the hydrocarbyl group of 1-10 carbon atom of straight or branched, the naphthenic hydrocarbon of 3-7 carbon atom, substituted aroma ring, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group, Z is hydrogen, the straight or branched alkyl of 1-10 carbon atom, the unitary of 1-20 carbon of straight or branched or polynary acyl group, the cyclic hydrocarbon radical of 3-7 carbon atom, substituting group aromaticacyl radical containing aromatic ring structure, or inorganic oxacid acyl group, M is sodium ion, potassium ion, ammonium ion, calcium ion, or magnesium ion.
12. a kind of compounds as claimed in claim 11, it is characterized in that: in the hydrocarbyl group of 1-10 carbon atom of straight or branched, optionally replaced by one or more substituted radical, described substituting group is selected from: the simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched.
13. a kind of compounds as claimed in claim 11, it is characterized in that: in the naphthenic hydrocarbon of 3-7 carbon atom, optionally replaced by one or more substituted radical, described substituting group is selected from: the simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched.
14. a kind of compounds as claimed in claim 11, is characterized in that: in substituted aroma ring, and substituted radical comprises halogen, the alkyl of a 1-3 carbon atom or hydrocarbyl ether.
15. a kind of compounds as claimed in claim 10, is characterized in that: described quinoline ring quilt
saturated, the unsaturated or fragrant rigid heterocyclic of five yuan or hexa-atomic substitutes.
16. a kind of compounds as claimed in claim 11, it is characterized in that: its compound name is called (3S, 5S)-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base)-3-fluoro-5-hydroxyl-6-in heptan olefin(e) acid sodium salt, its structural formula is as shown in 003
17. a kind of compounds as claimed in claim 11, it is characterized in that: its compound name is called (3S, 5R)-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base)-3-fluoro-5-hydroxyheptanoic acid sodium salt, its structural formula is as shown in 004
18. a kind of compounds as claimed in claim 11, it is characterized in that: its compound name is called (3S, 5S)-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base)-3-fluoro-5-hydroxyl-6-in heptan enoic acid hemicalcium salt, its structural formula is as shown in 005.
19. a kind of compounds as claimed in claim 11, it is characterized in that: its compound name is called (3S, 5R)-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base)-3-fluoro-5-hydroxyheptanoic acid half calcium salt, its structural formula is as shown in 006
20. 1 kinds of pharmaceutical compositions, arbitrary described compound or its salt or its ester, steric isomer or optically active isomer in the claim 11,16,17,18 or 19 containing significant quantity.
In 21. claims 11,16,17,18 or 19, arbitrary described compound is reducing the application in the medicine of blood lipid level for the preparation for the treatment of.
The application of arbitrary described compound in the medicine for the preparation of the atherosclerosis for the treatment of coronary heart disease, hyperlipidemia initiation or the hyperlipidemia of diabetes initiation in 22. claims 11,16,17,18 or 19.
23. a compound, its structural formula as shown in formula III,
Wherein, R1, R2 is hydrogen, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group, R3, R4 is hydrogen, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group, R5, R6, R7, R8, R9, R10, R11 is respectively hydrogen, hydroxyl, hydroxyl and carboxylate substituent groups formed by 1-3 carbon atom, the hydrocarbyl ether of 1-3 carbon atom, halogen, or the halohydrocarbon of 1-3 carbon atom, the hydrocarbyl group of 1-10 carbon atom of straight or branched, the naphthenic hydrocarbon of 3-7 carbon atom, substituted aroma ring, saturated or the unsaturated alkyl of the straight chain of 1-10 carbon atom, cyclopropyl, phenyl, methoxyl group, or oxyethyl group, Z is hydrogen, the straight or branched alkyl of 1-10 carbon atom, the unitary of 1-20 carbon of straight or branched or polynary acyl group, the cyclic hydrocarbon radical of 3-7 carbon atom, substituting group aromaticacyl radical containing aromatic ring structure, or inorganic oxacid acyl group.
24. a kind of compounds as claimed in claim 23, it is characterized in that: in the hydrocarbyl group of 1-10 carbon atom of straight or branched, optionally replaced by one or more substituted radical, described substituting group is selected from: the simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched.
25. a kind of compounds as claimed in claim 23, it is characterized in that: in the naphthenic hydrocarbon of 3-7 carbon atom, optionally replaced by one or more substituted radical, described substituting group is selected from: the simple substituted radical comprising 1-3 carbon atom of halogen atom, hydroxyl or straight or branched.
26. a kind of compounds as claimed in claim 23, is characterized in that: in substituted aroma ring, and substituted radical comprises halogen, the alkyl of a 1-3 carbon atom or hydrocarbyl ether.
27. a kind of compounds as claimed in claim 23, is characterized in that: described quinoline ring quilt
saturated, the unsaturated or fragrant rigid heterocyclic of five yuan or hexa-atomic substitutes.
28. a kind of compounds as claimed in claim 23, it is characterized in that: its compound name is called ((3S, 5S, E)-methyl-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base) the fluoro-5-methyl of-3--6-hydroxyl heptenoic acid methyl esters, its structural formula is as shown in 007
29. a kind of compounds as claimed in claim 23, it is characterized in that: its compound name is called (3S, 5R)-methyl-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base)-3-fluoro-5-hydroxyheptanoic acid methyl esters, its structural formula is as shown in 008
30. a kind of compounds as claimed in claim 23, it is characterized in that: its compound name is called (3S, 5S, E)-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base) the fluoro-5-of-3-(methanoyl)-6-heptenoic acid, its structural formula is as shown in 009
31. a kind of compounds as claimed in claim 23, it is characterized in that: its compound name is called (3S, 5R)-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base) the fluoro-5-of-3-(methanoyl) enanthic acid, its structural formula is as shown in 010
32. a kind of compounds as claimed in claim 23, it is characterized in that: its compound name is called (3S, 5S, E)-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base) the fluoro-5-of-3-(nicotinylsalicylic oxygen)-6-heptenoic acid, its structural formula is as shown in 011
33. a kind of compounds as claimed in claim 23, it is characterized in that: its compound name is called (3S, 5R)-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base) the fluoro-5-of-3-(nicotinylsalicylic oxygen) enanthic acid, its structural formula is as shown in 012
34. a kind of compounds as claimed in claim 23, it is characterized in that: its compound name is called (3S, 5S, E)-(3S, 3AR, 6S, 6AS)-6-(nitre oxygen base) hexahydro furyl also [3,2b] furans-3-base-7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base) the fluoro-5-methyl of-3--6-hydroxyl heptenoic acid esters-, its structural formula is as shown in 013
35. a kind of compounds as claimed in claim 23, it is characterized in that: its compound name is called (3S, 5R)-(3S, 3AR, 6S, 6AS)-6-(nitre oxygen base) hexahydro furyl also [3,2b] furans-3-base 7-(2-cyclopropyl-4-(4-fluorophenyl) quinoline pyridin-3-yl) the fluoro-5-hydroxyheptanoate of-3-, its structural formula is as shown in 014
36. 1 kinds of pharmaceutical compositions, arbitrary described compound or its salt or its ester, steric isomer or optically active isomer in the claim 23,28,29,30,31,32,33,34 or 35 containing significant quantity.
In 37. claims 23,28,29,30,31,32,33,34 or 35, arbitrary described compound is reducing the application in the medicine of blood lipid level for the preparation for the treatment of.
The application of arbitrary described compound in the medicine for the preparation of the atherosclerosis for the treatment of coronary heart disease, hyperlipidemia initiation or the hyperlipidemia of diabetes initiation in 38. claims 23,28,29,30,31,32,33,34 or 35.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105481838A (en) * | 2015-11-18 | 2016-04-13 | 北京万全德众医药生物技术有限公司 | Method for preparing pitavastatin lactone impurity |
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| CN102086184A (en) * | 2011-03-03 | 2011-06-08 | 上海应用技术学院 | 5-fluorine-substituted 4-hydroxyl-3,4,5,6-tetrahydro-2H-pyrane-2-ketone compound and preparation method thereof |
| CN102153463A (en) * | 2011-03-03 | 2011-08-17 | 上海应用技术学院 | 4-subsititued 3,5-dihydroxy carboxylic acid compound and preparation method thereof |
| CN104262248A (en) * | 2014-09-03 | 2015-01-07 | 上海应用技术学院 | Method for preparing 5-substituted 4,4-difluoro-3,5-dihydrocarboxylic acid and metal salts thereof |
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| CN102086184A (en) * | 2011-03-03 | 2011-06-08 | 上海应用技术学院 | 5-fluorine-substituted 4-hydroxyl-3,4,5,6-tetrahydro-2H-pyrane-2-ketone compound and preparation method thereof |
| CN102153463A (en) * | 2011-03-03 | 2011-08-17 | 上海应用技术学院 | 4-subsititued 3,5-dihydroxy carboxylic acid compound and preparation method thereof |
| CN104262248A (en) * | 2014-09-03 | 2015-01-07 | 上海应用技术学院 | Method for preparing 5-substituted 4,4-difluoro-3,5-dihydrocarboxylic acid and metal salts thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105481838A (en) * | 2015-11-18 | 2016-04-13 | 北京万全德众医药生物技术有限公司 | Method for preparing pitavastatin lactone impurity |
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